J. A. M. Smeitink
Boston Children's Hospital
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Featured researches published by J. A. M. Smeitink.
Nature Genetics | 2007
G.C. Scheper; Thom van der Klok; Rob J van Andel; Carola G.M. van Berkel; Marie Sissler; Joél Smet; Tatjana I Muravina; Sergey V Serkov; Graziella Uziel; Marianna Bugiani; Raphael Schiffmann; Ingeborg Krägeloh-Mann; J. A. M. Smeitink; Catherine Florentz; Rudy Van Coster; Jan C. Pronk; Marjo S. van der Knaap
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.
Neurology | 2002
Nicole I. Wolf; J. A. M. Smeitink
Background: In 1996 diagnostic criteria were published for adults with respiratory chain disorders. Modified criteria for children were also recently proposed. Objective: To facilitate and standardize diagnosis of respiratory chain disorders in children. Methods: A new classification has been developed, the Mitochondrial Disease Criteria (MDC), for the diagnosis of respiratory chain disorders in infants and children. It considers clinical, metabolic, imaging, and histopathologic features vs biochemical investigations of skeletal muscle. The criteria were applied to a group of 30 children. Results: The modified adult criteria and the MDC gave similar results, with 17 patients having a definite respiratory chain disorder. No patients reached this category using the original adult criteria. Conclusions: The proposed Mitochondrial Disease Criteria classification allows more precise definition of clinical and metabolic items and the independent scoring of muscle biochemical investigations before combining all findings to determine the overall diagnostic certainty.
Annals of Neurology | 1999
Ralf Triepels; L. van den Heuvel; Jan Loeffen; C. Buskens; R. Smeets; M.E. Rubio Gozalbo; Sandy Budde; Edwin C. M. Mariman; Frits A. Wijburg; Peter G. Barth; J. M. F. Trijbels; J. A. M. Smeitink
Leigh syndrome is the phenotypical expression of a genetically heterogeneous cluster of disorders, with pyruvate dehydrogenase complex deficiency and respiratory chain disorders as the main biochemical causes. We report the first missense mutation within the nuclear encoded complex I subunit, NDUFS7, in 2 siblings with neuropathologically proven complex I–deficient Leigh syndrome. Ann Neurol 1999;45:787–790
Journal of Inherited Metabolic Disease | 2001
J. van den Hout; Arnold J. J. Reuser; J. B. C. de Klerk; W.F.M. Arts; J. A. M. Smeitink; A.T. van der Ploeg
Pompe disease is a metabolic myopathy caused by deficiency of lysosomal acid α-glucosidase. In this report we review the first 36 weeks of a clinical study on the safety and efficacy of enzyme therapy aimed at correcting the deficiency. Four patients with infantile Pompe disease were enrolled. They received recombinant human α-glucosidase from transgenic rabbit milk. The product is generally well tolerated and reaches the primary target tissues. Normalization of α-glucosidase activity in skeletal muscle was obtained and degradation of PAS-positive material was seen in tissue sections. The clinical condition of all patients improved. The effect on heart was most significant, with an impressive reduction of the left ventricular mass index (LVMI). Motor function improved. The positive preliminary results stimulate continuation and extension of efforts towards the realization of enzyme therapy for Pompe disease.
European Journal of Human Genetics | 2005
Eva Morava; Suzan Wopereis; Paul Coucke; Gabrielle Gillessen-Kaesbach; Thomas Voit; J. A. M. Smeitink; Ron A. Wevers; Stephanie Grünewald
Congenital cutis laxa is a genetically heterogeneous condition presenting with loose and redundant skin folds, decreased elasticity of the skin, connective tissue involvement and a highly variable spectrum of associated features. The most common forms are inherited in an autosomal recessive or dominant fashion. Fibulin 5 and elastin mutations were detected in a limited number of patients, but in most cases the etiology is not known. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, we performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome, including a recently developed test for defective O-glycosylation. Here, we describe five patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay and neurological findings. Three of these five children have an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were found in the FBLN5 gene. In conclusion, we have identified a new combined glycosylation defect with a distinct clinical phenotype. Our results suggest that a combined defect of glycosylation might be a causative factor in congenital cutis laxa. This is the first report where abnormal N- and O-linked glycosylation is implicated in the etiology of cutis laxa syndrome.
Journal of Biological Chemistry | 2003
Stefan Kölker; Marina A. Schwab; Friederike Hörster; Sven W. Sauer; Angela Hinz; Nicole I. Wolf; Ertan Mayatepek; Georg F. Hoffmann; J. A. M. Smeitink; Jürgen G. Okun
Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure. It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. To elucidate whether methylmalonic acid is a respiratory chain inhibitor, we used spectrophotometric analysis of complex II activity in submitochondrial particles from bovine heart, radiometric analysis of 14C-labeled substrates (pyruvate, malate, succinate), and analysis of ATP production in muscle from mice. Methylmalonic acid revealed no direct effects on the respiratory chain function, i.e. on single electron transferring complexes I-IV, ATPase, and mitochondrial transporters. However, we identified a variety of variables that must be carefully controlled to avoid an artificial inhibition of complex II activity. In summary, the study verifies our hypothesis that methylmalonic acid is not the major toxic metabolite in methylmalonic acidurias. Inhibition of respiratory chain and tricarboxylic acid cycle is most likely induced by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.
Journal of Inherited Metabolic Disease | 1994
B. Fournier; J. A. M. Smeitink; L. Dorland; Rolf M.F. Berger; J. M. Saudubray; B. T. Poll-The
SummaryUntil recently peroxisomal disorders were considered to be extremely rare and the diagnostic procedures available for postanatal and prenatal diagnosis were not widely known. At present, 17 human disorders are linked to peroxisomal dysfunction. The clinical, biochemical and morphological peroxisome heterogeneity described in the different diseases illustrate that only combined analysis of all the different approaches will lead to a correct diagnosis and a coherent pathophysiological model to guide ongoing research. With the study of human peroxisomal diseasese, advances have been gained as to the function of the peroxisome in normal and pathological conditions. Genetic analysis of peroxisome biogenesis and research on peroxisomal targeting signals are now in progress. Peroxisomal disorders are usually classified according to the degree of biochemical impairment. In this paper, a tentative classification of peroxisomal disorders will be proposed, based on the degree of biochemical abnormalities combined with new data obtained on whether or not defective peroxisome assembly is involved: (1) disorders with peroxisome assembly deficiencies; (2) disorders with single enzyme deficiencies.The clinical onset and the major symptoms of the various disorders, and the recently discovered findings are discussed.
Journal of Inherited Metabolic Disease | 1992
J. A. M. Smeitink; F. A. Beemer; Marc Espeel; R. A. M. G. Donckerwolcke; Cornelis Jakobs; Ronald J. A. Wanders; R. B. H. Schutgens; Frank Roels; M. Duran; L. Dorland; Rolf M.F. Berger; B. T. Poll-The
The diagnosis of inborn errors of peroxisomal metabolism is based on a number of clinical and biochemical characteristics. The combination of skeletal abnormalities and peroxisomal dysfunction is seen in the rhizomelic form of chondrodysplasia punctata (RCDP) and in Zellweger syndrome (Wanders et al 1988). Recently two patients were described with a new type of chondrodysplasia punctata associated with the characteristic peroxisomal abnormalities observed in RCDP: (1) accumulation of phytanic acid in plasma, (2) a defect in plasmalogen synthesis, and (3) presence of the unprocessed form of peroxisomal thiolase protein (Pike et al 1990; Poll-The et all 1991)
Journal of Inherited Metabolic Disease | 1999
Ralf Triepels; J. A. M. Smeitink; Jan Loeffen; R. Smeets; C. Buskens; F. Trijbels; L. van den Heuvel
We present the cDNA sequence of the human mitochondrial acyl carrier protein NDUFAB1, a nuclear-encoded subunit of complex I of the mitochondrial respiratory chain. We obtained the NDUFAB1 cDNA using the cDNA sequence of the bovine mitochondrial acyl carrier protein. The human cDNA contains two putative translation initiation codons. The human NDUFAB1 protein contains a phosphopantetheine attachment site (DLGLDSLDQVEIIMAM), unique for acyl carrier proteins, and an EF-hand calcium binding domain (DIDAEKLMCPQEI). Transcripts of this gene are found in a wide range of human tissues. The highest expression levels were observed, in descending order, in adult heart, skeletal muscle and fetal heart. We subjected NDUFAB1 fibroblast cDNA of 20 patients with an isolated enzymatic complex I deficiency to mutational detection. No mutations in the NDUFAB1 open reading frame were observed. Future studies will answer whether mutations in the NDUFAB1 promoter or transcription elements are responsible for the observed complex I deficiency.
Journal of Inherited Metabolic Disease | 1993
M. Duran; E. R. Baumgartner; Terttu Suormala; L. Bruinvis; L. Dorland; J. A. M. Smeitink; B. T. Poll-The
Biotinidase deficiency (McKusick 253260) leads to a progressive deficiency of the vitamin biotin, an essential cofactor for the carboxylation reactions of pyruvate, propionyl-CoA, 3-methylcrotonyl-CoA and acetyl-CoA. This disease usually presents with neurological symptoms such as hypotonia, convulsions and ataxia, while skin rash and alopecia usually appear later. If treatment is delayed, irreversible brain damage such as optic atrophy and neurosensory hearing loss may result. The neurological dysfunction appears to be more severe than that observed in holocarboxylase synthetase (HCS) deficiency, propionic acidaemia or isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency